A JAK (Janus kinase) family is one type of tyrosine kinase and four types of JAK1, JAK2, JAK3 and Tyk2 (tyrosine kinase 2) are known, and they have an important role in cytokine signaling.
While the kinases of this family, except for JAK3, are widely expressed in tissues, the expression of JAK3 is restricted to immune cells. This does not conflict with that JAK3 plays an important role in signaling via various receptors for IL (interleukin)-2, IL-4, IL-7, IL-9, IL-15, IL-21, etc., by being non-covalently associated with the common γ chain (Non-Patent Documents 1 and 2).
Further, in a group of patients with an immune deficiency disease called X-linked severe combined immune deficiency (XSCID), a decrease in the JAK3 protein level or the gene defect of the common γ chain is observed. This indicates that the immunosuppression is caused by blocking of the signaling pathway via JAK3 (Non-Patent Documents 3 and 4). Animal tests indicate that JAK3 not only plays an important role in maturation of B- and T-lymphocytes but also is important to maintain the function of the T-lymphocytes. Accordingly, by controlling the immune response by means of such a mechanism, treatment of diseases relating to abnormal proliferation of T-lymphocytes such as organ transplant rejection or autoimmune diseases is expected.
Analyses of JAK1 knockout mice and JAK1 deficient cells indicate that JAK1 relates to signaling via various receptors for IFN (interferon)α, IFNβ, IFNγ, IL-2, IL-4, IL-6, IL-7, IL-15, etc. (Non-Patent Document 5). Accordingly, by controlling inflammatory responses via such signaling, treatment of diseases relating to activation of macrophages or lymphocytes such as autoimmune diseases and acute and chronic organ transplant rejection is expected.
Analyses of JAK2 knockout mice and JAK deficient cells indicate that JAK2 relates to signaling via various receptors for EPO (erythropoietin), thrombopoietin, IFNγ, IL-3, GM-CSF, etc. (Non-Patent Document 6, 7 and 8). Such signaling is considered to relate to differentiation of precursor cells of erythrocytes, platelets, etc. in bone marrow. Meanwhile, it is suggest that the mutation which is defined by a valine-to-phenylalanine substitution at amino acid position 617 in JAK2, is associated with myeloproliferative neoplasms (Non-Patent Document 6). Thus, by regulating differentiation of bone marrow precursor cells by means of such a mechanism, treatment of myeloproliferative neoplasms is expected.
Further, it has been reported that CP-690,550 which is a JAK inhibitor has an effect to improve the clinical condition of rheumatoid arthritis and psoriasis in clinical trials (Non-Patent Documents 9 and 10) and has an effect to suppress rejection in monkey renal transplantation models and airway inflammation in mouse asthma models (Non-Patent Documents 11 and 12). From these findings, suppression of immune activity by a JAK inhibitor is considered to be advantageous for prevention or treatment of organ transplant rejection, graft versus host reaction after transplantation, autoimmune diseases and allergic diseases. Compounds having a JAK inhibitory effect other than CP-690,550 are known e.g. in the following reports (for example, Patent Documents 1 to 14), and further development of pharmaceutical agents has been desired.
In a patent document published after filing of the application on the basis of which the priority of the present application is claimed, tricyclic pyrrolopyridine compounds having a JAK inhibitory effect are reported, however, the patent document failed to specifically disclose the compounds of the present invention (Patent Document 15).